[JBC] Better Bispecific Antibodies

Bispecific antibodies, which simultaneously recognize two different antigens, hold great therapeutic potential, but their broad application has been hindered by difficulties in developing stable antibody platforms, favorable pharmacokinetic properties and feasible large-scale manufacturing protocols. In this study, researchers from Genentech Inc. have taken a step in overcoming these problems, improving upon a previously used small-scale strategy, known as “knobs-into-holes,” that employed sterically complementary mutations in the antibody heavy chain CH3 domain to promote heavy chain heterodimerization with a single common light chain to prevent heavy chain/light chain mispairing. The researchers adapted this technology into a two-part strategy that consists first of small-scale generation of bispecific antibodies lacking a common light chain and hinge disulfides to facilitate proof-of-concept studies, followed by the identification of a common light chain-bispecific antibody for large-scale production with high purity and yield. They used their strategy to successfully generate a bispecific antibody that inhibits the activation of the high affinity IgE receptor FcεRI by cross-linking it with the inhibitory receptor FcγRIIb; this antibody displayed similar pharmacokinetic properties to regular human IgG antibodies, showing its promise as a therapeutic agent for asthma and other allergic diseases.

Development of a Two-part Strategy to Identify a Therapeutic Human Bispecific Antibody That Inhibits IgE Receptor Signaling